Methylthioninium chloride (MTC) [3,7-bisdimethylaminophenazothionium chloride, C16H18ClN3S, 319.85 g/mol], commonly known as methylene blue, was prepared for the first time in 1876 (The Merck Index, 13th edition, Merck & Co., Inc., 2001, entry 6085). Various synthetic methods for MTC are known and have recently been summarized in WO 2006/032879. WO 2006/032879 also discloses a number of applications of methylene blue, which include use as a medical dye, as a redox indicator, as an antiseptic, for the treatment and prevention of kidney stones, and for the treatment of melanoma, malaria, and viral infections. MTC has also been used as an oxidizing agent and as an antidote in the case of carbon monoxide, nitrite and aniline poisoning.
MTC has also been proposed for treatment of mild to moderate dementia of the Alzheimer's type (DAT), also known as Alzheimer's disease (AD), a severe irreversible neurodegenerative disease resulting in complete loss of mental faculties.
For example WO96/30766 describes the use of tau aggregation inhibitors—including MTC for the treatment of various diseases of protein aggregation including AD. Other disclosures of phenothiazines in the area of neurodegenerative disorders include WO 02/075318, WO 2005/030676, WO 02/055720, WO2007110627, WO2009/060191, WO2009/044127.
MTC, in common with many solid substances useful as active pharmaceutical ingredients, exhibits polymorphism, i.e. it exists in more than one physical form, known as polymorphs, which are typically different crystalline and hydrate forms of the drug substance. Hydrates are crystalline solids containing differing amounts of water incorporated into the crystal structure.
The Fluka catalogue states in very general terms that MTC may contain up to 22% water (Fluke Catalogue 1997/1998, Fluka Chemie AG, 1997]. MTC is generally considered to exist as a trihydrate, but this was disputed as long as 80 years ago, and non-specific adsorption of water by MTC was proposed instead (H. Wales, O. A. Nelson, J. Am. Chem. Soc. 45 (1923) 1657). A pentahydrate including single crystal X-ray data was described later by several authors (J. O. Warwicker, J. Chem. Soc. (1955) 2531 and H. E. Marr III, J. M. Stewart, M. F. Chiu, Acta Cryst. B29 (1973) 847). This pentahydrate consists of π-stacked columns of MTC molecules arranged in planes perpendicular to the α-axis of the crystal. The water molecules and chloride ions are located between these layers, whereas the chloride ions are concentrated in planes almost perpendicular to the water planes and parallel to the axis of the columns. The chloride ions are coordinated with three hydrogen bonds from 3/2 water molecules. Presumably, the same structure was earlier attributed to a tetrahydrate (W. H. Taylor, Z. Krist. 91 (1935) 450).
The MTC polymorph known as “Form A” has been identified as a pentahydrate and “Form B” as a dihydrate. Form A is considered stable at high relative humidity (RH) down to approximately 35% RH. High kinetic stability of the pentahydrate (Form A) is even observed down to RH less than 20%.
Several other polymorphs of MTC, referred to as Forms C, D and E, have also been identified. It has been found that the dihydrates B and D are metastable forms over the whole range of water activity and are only kinetically favoured under certain preparation conditions. Form B seems to be the product of incomplete drying of Form A. Form D was obtained in precipitation experiments. No anhydrate form has been identified, but X-ray diffractograms include peaks that cannot be attributed to any of the five known forms. It is therefore likely that the polymorphism of MTC is even more complex than has hitherto been established.
Prior filed unpublished patent applications PCT/IB2010/002526 and PCT/IB2010/002543 relate to crystalline forms of diaminophenothiazines and provide more detailed information on the characteristic diffraction peaks of the various polymorphic forms. The disclosure of these applications (and corresponding priority documents) particularly in respect of such patterns and peaks is specifically incorporated herein.
It is known that the polymorphic forms of a drug molecule may have different chemical and/or physical properties. For example, polymorphs can differ substantially in melting point, chemical reactivity, particle size, shape, flow characteristics, caking, degree of hydration or solvation, optical and electrical properties vapour pressure, and density. As a result, certain polymorphs of a drug molecule can be more stable than others under given environmental conditions.
MTC has a number of properties which render its formulation into a dosage form quite difficult. The distinct blue colour presents processing and cleaning challenges. More significantly, the existence of numerous polymorphic forms is problematic. In particular, the physical stability of the polymorphic Form A is problematic, as during heating and/or storage it can be converted into the polymorphic Forms B and D. The interconversion of the individual crystalline polymorphic forms of MTC in a medicament, during manufacture and/or storage is undesirable as it is a general regulatory requirement that the identity of the medicament must be guaranteed throughout its entire shelf life.
The limited stability domain of all MTC polymorphic forms requires an innovative approach to formulation to produce a consistent dosage form. The product quality should be consistent and reproducible at the time of manufacture and on storage at temperatures and relative humidity levels typically encountered in most countries of the world. One may additionally seek other desirable properties in a formulation such as fast dissolution so that the tablet quickly dissolves and the medicine is available for absorption, and also properties such as good compressibility and robustness, and ease of manufacture. Accordingly, good storage stability and fast dissolution are important and desirable attributes for immediate release tablet formulations and capsules.
Processes used for tablet formulation and film coating often require the use of heat accompanied by low humidity during the drying process. Clearly, for a material such as MTC, with complex polymorphism, such processes can lead to changes in the physical form of the active ingredient, and hence potentially to instability in the performance of the product.
The most commonly used method for the preparation of solid dosage forms is wet granulation. This involves adding a granulating fluid to a powder. The granulating fluid may be water or some other solvent that is sufficiently volatile that it can subsequently be removed by drying. The granulating fluid may also include a binder. Once the solvent has been removed, the resulting mass is milled.
Wet granulation is often preferred over direct compression because wet granulation is more likely to overcome any problems associated with the physical characteristics of various ingredients in the formulation. Wet granulation provides material which has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form. The content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. Segregation of the drug from excipients is also avoided.
In direct compression, the individual constituents of the composition to be compressed are mixed without previous granulation and then directly compressed. Whilst this appears to be an elegant and simple process, it is difficult to obtain with it commercially usable tablets which have sufficient strength yet which also disintegrate sufficiently rapidly after administration. Also, many active substances cannot be processed by direct compression since they cannot be compressed without a granulation step.